U.S. patent number 6,458,841 [Application Number 09/734,096] was granted by the patent office on 2002-10-01 for topical and oral delivery of arginine to cause beneficial effects.
This patent grant is currently assigned to New England Property Holdings, LLC. Invention is credited to Eric T. Fossel.
United States Patent |
6,458,841 |
Fossel |
October 1, 2002 |
Topical and oral delivery of arginine to cause beneficial
effects
Abstract
The use of orally administered L-arginine in conjunction with a
topical preparation for producing enhanced blood flow in tissue
thus causing beneficial effects such as warming cold tissue of the
hands and feet, promoting hair growth on bald scalp tissue,
promoting healing of superficial Ilcers such as leg ulcers in
persons with diabetes, and overcoming male erectile failure
(impotence) is disclosed. Specifically, use of orally administered
L-arginine in conjunction with this is topical preparation provides
local delivery of the amino acid L-arginine, an important
biological precursor to the main substance which is responsible for
relaxation of blood vessels permitting enhancement of blood flow.
In the preferred embodiments, the L-arginine is provided so that it
can be topically applied to the cold tissue. The preparation also
contains an agent which aids in the transfer of L-arginine into the
tissue. In the preferred embodiments this agent overcomes the
resistance to transfer caused by the high charge density of
L-arginine. In the preferred embodiments this means is high ionic
strength created by addition of sodium chloride. This preparation,
when topically applied to cold tissue, warming begins within 10 to
45 minutes and is sustained for periods as long as 2 to 18 hours.
Further this preparation when applied nightly to bald scalp
tissue-for a period of time causes substantial growth of hair on
the bald scalp, causes the healing of superficial ulcers such as
leg ulcers and overcomes impotence.
Inventors: |
Fossel; Eric T. (South Hero,
VT) |
Assignee: |
New England Property Holdings,
LLC (Burlington, VT)
|
Family
ID: |
25468298 |
Appl.
No.: |
09/734,096 |
Filed: |
December 11, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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936189 |
Sep 17, 1997 |
6207713 |
|
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Current U.S.
Class: |
514/565; 424/401;
424/439; 424/450 |
Current CPC
Class: |
A61K
8/14 (20130101); A61K 8/44 (20130101); A61K
31/198 (20130101); A61Q 7/00 (20130101); A61Q
19/00 (20130101) |
Current International
Class: |
A61K
8/30 (20060101); A61K 8/44 (20060101); A61K
31/198 (20060101); A61K 31/185 (20060101); A61K
8/14 (20060101); A61Q 19/00 (20060101); A61Q
7/00 (20060101); A61K 031/195 (); A61K 006/00 ();
A61K 047/00 (); A61K 009/127 () |
Field of
Search: |
;514/565
;424/401,450,439 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Cooper et al., "Transdermal Delivery of Drugs", vol. II, editors
Kydonieus and Berner, CRC Press, Inc., Boca Raton, FL, 1987, pp.
57-52. (Library of Congress Card No. 86-2585)..
|
Primary Examiner: Criares; Theodore J.
Attorney, Agent or Firm: Lorusso & Loud
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATION
This is a Divisional application of U.S. Ser. No. 08/936,189, filed
Sep. 17, 1997, now U.S. Pat. No. 6,207,713 the contents of which
are incorporated herein by reference.
Claims
What is claimed is:
1. A method of promoting hair growth by delivering a nitric oxide
releasing substance selected from a member of the group consisting
of L-arginine, L-arginine salts and L-arginine derivatives
comprising the step of orally administering to the body a delivery
vehicle for the substance, said delivery vehicle containing an
effective amount of the substance and a concentration of ionic salt
sufficient to create a hostile biophysical environment which causes
the substance to migrate from said delivery vehicle to the
surrounding tissue where it is absorbed.
2. The method of claim 1 wherein the vehicle is selected from a
member of the group consisting of capsules, tablets, and liquids
containing the substance.
3. The method of claim 1 comprising the further step of topically
applying a delivery vehicle containing an effective amount of the
substance and a concentration of ionic salt sufficient to create a
hostile biophysical environment which causes the substance to
migrate from the vehicle to the selected area of skin where hair
growth is desired.
4. The method of claim 3 wherein the delivery vehicle that is
topically applied is selected from the group consisting of topical
creams, topical liquids, topical lotions and topical ointments.
5. The method of claim 3 wherein the delivery vehicle that is
topically applied is hydrophobic.
6. The method of claim 3 wherein a transdermal patch containing the
delivery vehicle that is topically applied is applied to the
selected area of the skin.
7. The method of claim 3 wherein the delivery vehicle that is
orally administered further comprises L-arginine from 0.5-30 g/day
and the delivery vehicle that is topically administered further
comprises water from 20-80%, mineral oil from 3-18%, glyceryl
stearate from 0.5-12%, squalene from 0.2-12%, cetyl alcohol from
0.1-11%, propylene glycol stearate from 0.1-11%, wheat germ oil
from 0.1-6%, glyceryl stereate from 0.1-6%, isopropyl myristate
from 0.1-6%, stearyl stearate from 0.1-6%, polysorbate from 60
0.1-5%, propylene glycol from 0.05-5%, tocopherol acetate from
0.05-5%, collagen from 0.05-5%, sorbitan stearate from 0.05-5%,
vitamin A&D from 0.02-4%, triethanolamine from 0.01-4%,
methylparaben from 0.01-4%, aloe vera extract from 0.01-4%,
imidazolidinyl urea from 0.01-4%, propylparaben from 0.01-4%, bha
from 0.01-4%, L-arginine hydrocholide from 0.25-25%, sodium
chloride from 0.25-25%, and magnesium chloride from 0.25-25%.
8. The method of claim 7 wherein the delivery vehicle that is
topically applied further includes choline chloride from
0.25-25%.
9. The method of claim 7 wherein the delivery vehicle that is
topically applied further comprises L-arginine glutamate
(0.25-25%).
10. A method of promoting hair growth by delivering a nitric oxide
releasing substance selected from a member of the group consisting
of L-arginine, L-arginine salts and L-arginine derivatives
comprising the step of orally administering to the body a delivery
vehicle for the substance, said delivery vehicle containing an
effective amount of the substance and a concentration of ionic salt
sufficient to create a hostile biophysical environment which causes
the substance to migrate from said delivery vehicle to the
surrounding tissue where it is absorbed, in conjunction with the
step of topically applying to a selected area of skin a topical
delivery vehicle containing an effective amount of the substance
within a liposome, so that the liposome containing the substance
migrates from the delivery vehicle into the skin where the
substance is absorbed by tissue.
Description
BACKGROUND
1. Field of the Invention
This invention relates to the use of L-arginine orally alone or in
conjunction with topical application of a cream, gel, or other
vehicle which contains substances such as L-arginine which delivers
these substances into tissue for the purpose of producing
beneficial effects such as warming of cold or cool tissues, growth
of hair on the scalp, healing of leg ulcers secondary to diabetes
or confinement to bed, relief of impotence, as well as beneficial
effects through restoration of natural mechanisms based on
improvement of local blood supply.
2. Prior Art
Approaches to improving local blood flow have been many and consist
of both systemic and topical approaches. Many beneficial effects
could be obtained should improvement in local blood flow be
achieved since impairment of local blood flow causes a variety of
negative consequences. Among these are cold hands and feet,
baldness, leg ulcers, certain forms of impotence, as well as a
variety of other things. Approaches to warming cold tissue
including cold hands, fingers, feet and toes constitute one section
of the prior art. Many persons suffer from cold hands, feet or
other body parts. This is often caused by insufficient blood flow
in the cold tissue. Previously cold hands or feet have been treated
by wearing warm socks or gloves, sometimes even socks or gloves
which are mechanically heated. The use of hot packs and glove or
shoe inserts which generate heat through chemical reactions has
also been a potential solution. Certain liniments which are
essentially irritants, such as those containing the red pepper
derived substance, capsicum fall into this category. More recently,
topical creams containing nitroglycerine have been used. See H.
Natsuda et al., Ryumachi 34, 849 (1994). All of these approaches
work at one level or another though are often extremely transient
in nature. Nitroglycerine creams also have the disadvantage that
nitroglycerine is a cardioactive drug, raising concerns of effects
on the heart.
It has been recognized that deficiencies in blood flow in the scalp
occur in male pattern baldness. See G. Duplechain et al., J.
Lousiana State Med Soc. 146, 7 (1994); P Klemp et al., J Invests
Dermatol 95, 725 (1989); S Toshitani et al., J Dermatol 17, 240
(1990). Topical minoxidil has been used as an agent for hair growth
in male pattern baldness with varying results. Though the
suggestion has been made that minoxidil operates through increase
in the blood supply to the scalp, many investigators have failed to
show such an effect. See E de Boer et al., Acta Dermato-
Venereoligica 68, 271 (1988); C Bunker et al., British J Derm 117,
668 (1987).
The fundamental fact that cold tissue of the hands, fingers, feet
and toes as well as other cold tissue is caused by insufficient
blood flow to the tissue has been suggested. It has further been
suggested by some that the use of increased blood flow through
relaxation of blood vessels, particularly small and very small
vessels may be of use in warming cold tissue. However reasonable
this suggestion, many attempts to demonstrate warming by use of
agents which produce vasodilation and therefore increased blood
flow have produced negative results. See N Dietz et al., J Appl
Physiol 76, 2047 (1994); S Whitmore et al., J Rheumatol 22, 50
(1995); S Singh et al., Eur J Clin Invest 25, 182 (1995). The only
report of modest temporary success involved the use of
nitroglycerine. See H Natsuda et al., Ryumachi 34, 849 (1994). The
use of the nitric oxide precursors such as L-arginine to produce
warming secondary to vasodilation has been suggested. And a variety
of indirect and non-definitive experiments have been conducted
using oral administration. See M. Sonntag et al., Pflugers Arch
420, 194 (1992); A. Agostoi et al., Int J Clin Lab Res 21, 202
(1991). Thus, while the literature contains suggestions that
vasodilation by administration of oral L-arginine, the precursor of
nitric oxide (endothelium ependent relaxing factor), no reports
exist of success in producing warming of tissue using this agent.
In fact Dietz (see N Dietz et al., J Appl Physiol 76, 2047 (1994))
concludes from his data that "These data suggest that NO (nitric
oxide) does not play a major role in cutaneous vasodilation during
body heating in humans." Further Singh (see S Singh et al., Eur J
of Clin Invest 25, 182 (1995)) in a study of patients with
Raynaud's phenomenon (severely cold hands and/or feet) concludes
that L-arginine failed to cause vasodilation (and therefore
warming) in patients with Raynaud's phenomenon.
The literature contains no suggestions or examples of the use of
L-arginine in any mode of administration for the growth of hair in
male pattern baldness, healing of ulcers of the skin, impotence or
for any other purpose.
It has long been recognized that impaired blood flow to the penis
is a major cause of erectile failure (impotence) in men. See A
Moradian et al. Am J. Med 85, 748, (1988); T Hwang et al. J
Formosan MedAssoc 89, 992 (1990). Further it has been recognized by
using isolated tissue in vitro and in animal experiments that
nitric oxide is an important mediator of relaxation of the vessels
in penile cavernous tissue. See H Kirkeby et al. Acta Physiol Scand
149, 385 (1993). Topical nitroglycerine has been used in the
treatment of impotence because of its ability to dilate vessels.
The results were inconclusive and the treatment not well tolerated
because of the cardiac response to nitroglycerine. See S Negelev J
Urology 143, 586 (1990).
It was discovered that topical application of the nitric oxide
precursor, L-arginine, in its various forms including orally alone
or in conjunction with a variety of topical preparations, either by
themselves or with other agents to aid in penetration such as a
high ionic strength environment, neutralization of its charge in a
complex or by other means, or included in a liposome or other
biological carrier, when administered to cold or cool tissue causes
a substantial and prolonged warming effect in the tissue, grow hair
on bald scalp, facilitate healing of superficial ulcers such as leg
ulcers and overcome impotence in many subjects.
In accordance with that invention, oral arginine by itself or in
combination with a penetrating cream containing L-arginine at a
concentration sufficient to produce an effect and sodium chloride
or other salt at a concentration sufficient to create a hostile
biophysical environment for the L-arginine in the cream is applied
to the cold or cool tissue alone and/or in conjunction with oral
arginine, exerts a warming effect which is prolonged, often lasting
from 2-18 hours. In persons with very cold tissue (for example
22.degree. C.) this warming effect can have a magnitude of
10.degree. C. or more.
Further, in accordance with this invention, oral L-arginine alone
or in conjunction with a penetrating cream containing L-arginine in
a concentration sufficient to produce the desired effect along with
sodium chloride or other salts at a concentration sufficient to
produce a hostile biophysical environment when applied to bald
areas of the scalp nightly either alone and/or in conjunction with
oral arginine, produced growth of new hair within one month and
substantial growth of hair within 3-4 months.
Yet further, in accordance with this invention, oral arginine alone
or in conjunction with a penetrating cream containing L-arginine in
a concentration sufficient to produce the desired effect along with
sodium chloride or other salts at a concentration sufficient to
produce a hostile biophysical environment when applied locally as
the cream directly to the penis either alone and/or in conjunction
with oral arginine, was effective in overcoming impotence.
Consequently, with the discovery of the present invention, a means
to warm cold and cool tissue, a problem shared by many, was
developed for improving this uncomfortable and often painful
problem in human health has been found. Further with the discovery
of the present invention, a means to restore hair growth on a bald
portion of scalp has been found. Still further, with the discovery
of the present invention, a means effect healing of superficial
ulcers such as leg ulcers has been found. Yet further, with the
discovery of the present invention, a means to overcome impotence
in many men has been found.
These and other objects and features of the present invention will
become apparent to those skilled in the art from reading the
description of the invention, which follows.
SUMMARY OF THE INVENTION
Accordingly, several objects and advantages of the instant
invention are to warm cold tissue in hands, feet or other tissue by
increasing blood flow in the tissue means of enhancement of the
body's natural mechanisms. It is further an object and advantage of
the instant invention to prophylactically prevent tissue from
becoming cold by use prior to entering into situations which induce
cold hands and feet such as skiing or other winter outdoors
activities. It is further an object and advantage of the instant
invention to induce the growth of hair on bald portions of human
scalp by means of enhancement of the body's natural mechanisms. It
is yet another object of the instant invention to induce healing of
superficial ulcers of the limbs by means of enhancement of the
bodys natural mechanisms. It is still further another object of the
instant invention to provide a means for overcoming impotence in
many men.
In preferred embodiments, the delivery vehicles are capsules or
tablets containing L-arginine used alone or in conjunction with a
penetrating cream. In the cream the L-arginine is present as
L-arginine hydrochloride in a concentration sufficient to produce
the desired effect and the agent which creates the hostile
biophysical environment is sodium chloride at a concentration
sufficient to aid in tissue absorption.
PREFERRED EMBODIMENTS
The preferred embodiment consists tablets or capsules containing
200-500 mg of L-arginine to be used alone or in conjunction with a
base cream with the properties of excellent absorption into the
skin which also contains L-arginine hydrochloride (15% w/v) and
sodium chloride (10% w/v). The components of the base cream may be
those commonly found in hand creams. The purpose of L-arginine
hydrochloride is to provide a precursor to the molecule, nitric
oxide, NO. The purpose of the sodium chloride is to provide a high
ionic strength environment for the highly charged molecule,
L-arginine. The base cream containing L-arginine and sodium
chloride is the agent which is applied to the hands and/or feet to
produce to produce a warming effect in the tissue, to produce hair
growth or to effect healing of ulcers such as leg ulcers, or
directly to the penis in order to aid in overcoming impotence.
The treatment consisting of oral administration of capsules or
tablets containing Larginine used alone or in conjunction with the
cream acts effectively to warm cold tissue such as hands, fingers,
feet, toes or other tissue when applied to the tissue and rubbed
into the tissue to assure maximal absorption. The warming effect,
caused by increased blood flow in the tissue is not instant but
begins within 5 to 20 minutes. The effect is long lasting. Often
the tissue remains warm for more than 2 to 18 hours. The treatment
consisting of oral administration of capsules or tablets containing
L-arginine used alone or in conjunction with the cream acts
effectively to induce hair growth on bald human scalp when applied
nightly to the bald area each night for several months. Hair growth
is naturally a slow process. However, substantial hair growth is
achieved over large areas of scalp with results becoming evident in
a few weeks and substantial within several months. The cream
further acts to promote healing of superficial ulcers such as those
sometimes found on the legs of persons with severe diabetes.
Application twice daily for a period. of two weeks causes
substantial healing and in many cases complete healing is achieved
within this time period or slightly longer (3-4 weeks). Further the
treatment consisting of oral administration of L-arginine used
alone or in conjunction with the cream when carried out daily for a
period of 7-10 days and then maintained with daily administration
causes substantial relief from impotence in many men.
Other Embodiments
Other Active Agents
While L-arginine hydrochloride is the preferred active agent
because it is the agent in nature itself, it is non-toxic, is
highly soluble and it is inexpensive, other agents could be used
which are also precursors or donors of nitric oxide. These include
the salt, arginine glutamate, the salt, arginine butyrate, and
esters of arginine such as arginine ethyl ester or arginine butyl
ester as well as other donors of nitric oxide. In the case an
alternative active agent were used it would be simply substituted
for L-arginine in a delivery preparation and the preparation used
as in the case of the L-arginine preparation.
Other Means of Effecting Absorption
A variety of means for effecting absorption of the active agent
from the topical cream might be envisioned. One principle behind
the absorption of a highly charged molecule such as L-arginine into
tissue is to either create a biophysically hostile environment in
the delivery vehicle such that L-arginine would prefer to be in
tissue, or to package L-arginine in such a way that it is carried
into tissue or neutralize its charge by derivitization or forming a
neutral salt. Examples of biophysically hostile environments,
include but are not limited to, high ionic strength, high or low
pH, and highly hydrophobic environments. Examples of packaging
which would be carried into tissue includes liposomes or emulsions
of collagen, collagen peptides or other components of skin or
basement membrane. Examples of neutralization of charge include the
salt, arginine glutamate which is electronically neutral.
In each case of creating a hostile biophysical environment for the
active agent, the agent was added to an appropriate preparation. In
the case of creating a high ionic strength ions such as but not
limited to sodium chloride, potassium chloride, choline chloride,
lithium chloride, alone or in combination were added in high
concentration. Other highly charged molecules such as polylysine,
polyglutamine, polyaspartate or copolymers of such charged amino
acids may be used to create the hostile biophysical environment.
Alternatively a hostile biophysical environment may be created by
placing the highly charged L-arginine in an hydrophobic, oily
environment such as in an oil-based cream containing little or no
water.
EXAMPLE 1
In this example a person with very cold fingers was provided with
the above warming cream consisting of a delivery vehicle of
penetrating cream, L-arginine hydrochloride (15% w/v), and sodium
chloride (10% w/v). The surface temperature of the subject fingers
of the left hand varied from 21 to 24.degree. C. The warming cream
was applied through rubbing into the skin. Surface temperatures of
each finger were measured each 15 minutes for the initial hour. At
15 minutes following administration of the warming cream the effect
had begun to occur with surface temperatures or various fingers
rising to 26 to 29.degree. C. The maximal effect was reached by 45
minutes with surface temperatures of various fingers becoming 31 to
34.degree. C. The effect was sustained at least 4 hours.
EXAMPLE 2
In this example a 53 year old man with baldness consisting of a
severely receding hairline as well as large "bald spot" on the top
rear of his head was provided with a penetrating cream containing
L-arginine hydrochloride (15% w/v) and sodium chloride (10% w/v).
The cream was applied to the bald areas each night before going to
bed and was rubbed in extensively for maximal absorption. New hair
growth was noted within 2-3 weeks. Within 4 months the receding
hairline (previously 4 cm of bald skin) had returned to normal and
the "bald spot" previously more than 7 cm in diameter had been
reduced to an area of less than 2 cm with even this area showing
some new hair growth.
EXAMPLE 3
In a 54 year old man with a history of impotence administration of
1.5 g L-arginine daily in the form of oral capsules combined with
twice daily administration of a penetrating cream containing
L-arginine hydrochloride (15% w/v) and sodium chloride (10% w/v)
directly to the penis for 7 days brought initial relief from the
symptoms of impotence and allowed the subject to resume normal
sexual activity.
This relief of symptoms was maintained by continuation of the
treatment daily.
Accordingly, it can be seen that in the present invention I have
provided a method and agents, which when applied to cold, and often
painful tissue, an increase in skin temperature results through
utilization of one of the body's own mechanisms for producing
warmth. This effect is achieved by providing the biochemical
substrate at the local site from which the controlling substance,
nitric oxide, is produced. Nitric oxide causes increases in local
blood flow which results in warming. Further, it can be seen that
in the present invention I have provided a method and agents which
when applied to bald scalp causes hair growth through utilization
of one of the body's own mechanisms. This effect is achieved by
providing the biochemical substrate at the local site from which
the controlling substance, nitric oxide is produced. Nitric oxide
causes increases in local blood flow which enables the growth of
hair. Still further it can be seen that in the present invention I
have provided a method and agents which when applied to leg ulcers
cause healing through use of the body's own mechanisms. Yet still
further, it can be seen that in the present invention I have
provided a method and agents which when applied to a person with
impotence causes overcoming of impotence by use of the body's own
mechanisms. This effect is achieved by providing the biochemical
substrate at the local site from which the controlling substance,
nitric oxide is produced. Nitric oxide causes increases in local
blood flow allowing the body's own healing cells and substances to
reach the ulcer site.
Although the description above contains many specificities, these
should not be construed as limiting the scope of the invention but
as merely providing illustrations of some of the presently
preferred embodiments of this invention. Various other embodiments
and ramifications are possible within this scope. Thus the scope of
the invention should be determined by the appended claims and their
legal equivalents, rather than by the examples given.
* * * * *